Proteolytic control of local inflammatory macrophage proliferation Atherosclerosis and its complications remain the leading cause of morbidity and mortality worldwide, and the increased incidence of obesity and associated cardiovascular disease further exacerbates this major health problem. In human atherosclerotic lesions and obese adipose tissue, and in mouse models, macrophages accumulate in large numbers within lesions, and interference with inflammatory macrophage accumulation can reduce lesion formation, adipose tissue inflammation and insulin resistance. Recent findings suggest that local macrophage proliferation, rather than monocyte recruitment, is the key event, but mechanisms initiating the proliferative response in disease are poorly understood. This proposal will address this knowledge gap by building on novel observations made by our laboratory that identify proteolytic cleavage by the transmembrane protease ADAM17 of the cell surface form of macrophage colony stimulating factor (csCSF-1), a potent stimulant of monoycte and macrophage proliferation and survival, as a major event controlling proliferation of macrophages recruited to inflammatory sites. We propose three specific aims 1. Test the impact of neutrophil deletion of ADAM17 on inflammatory macrophage proliferation under conditions of acute and chronic inflammation; 2. Investigate contributions of iRhom proteins that regulate ADAM17, and compartmentalization of csCSF-1, to control of csCSF-1 release from neutrophils; and 3. Directly test the role of ADAM17-mediated cleavage of csCSF-1 in macrophage proliferation within atherosclerotic lesions and inflamed adipose tissue, and develop and test novel strategies to selectively prevent its cleavage. Thus our proposed studies will clarify molecular mechanisms controlling macrophage proliferation in acute and chronic inflammation, and have the potential to develop strategies to interfere with macrophage accumulation, a major factor driving cardiovascular disease.